New phthalimides and methods for their preparation



ilnited htates Patent 3,@Z5,3li@ Patented Mar. 13, 1962 tine 3,025,300NEW PHTHALIMHDES AND METHODS FOR THEM PREPARATION Charles FerdinandHuehner, Chatham, N..'l., assignor to Cilia Pharmaceutical Products,Inc, Summit, N.J., a corporation of New Jersey N Drawing. Filed Dec. 14,1955, Ser. No. 552392 6 Claims. (Cl. 260-294) This is acontinuation-in-part of my copending applications, Serial No. 448,123,filed August 5, 1954, now abancloned, and Serial No. 529,341, filedAugust 18, 1955.

This invention relates to a new series of chemical compounds. Moreparticularly, this invention is concerned with newN-(2-disubstituted-aminoalkyD-1,2,3,4-tetrachlorophthalimides.

The compounds of this application may be represented by the formula:

NwHanNmm wherein R and R are members selected from the group consistingof lower alkyl radicals and when taken together, comprise the alkyleneand oxaalkylene radicals containing from 4 to 5 carbon atoms, and n is awhole number from 2 to 3.

In my copending application Serial No. 448, 123, I have disclosedcertain quaternary N-(substituted-aminoalkyl)-tetrachloroisoindolinesand methods for their manwherein R, R and R are lower alkyl radicals orR -N-R taken together is a heterocycloaliphatic radical containing from4 to 5 carbon atoms such as l-pyrrolidinyl, piperidino or morpholino, Ais a therapeutically useful anion from acids such as hydrochloric,hydrobromic, hydriodic, methanesultonic, acetic, citric, tartaric,p-toluenesulfonic or from esters such as dialkyl sulfates, i.e. dimethylsulfate and the like, and n is 2 or 3.

The quaternary N-(substituted-arninoalkyD-tetrachloroisoindolines may beprepared by treating aZ-(disubstituted-aminoalkyl)-4,5,6,7-tetrachloroisoindoline with aquaternizing agent capable of introducing a lower alkyl residue,especially reactive esters of lower alkanols, such as lower alkylhalides, lower alkyl p-toluenesulfonates, or di(lower)alkyl sulfates.Quaternary salts of other acids such as sulfuric, acetic, tartaric,citric, benzoic and the like are produced, for example, from the iodidesby treatment of the quaternary iodide in alcoholic solution with thesilver salt of the desired acid. Alternatively, the free quaternaryhydroxide may be formed by treating the quaternary halide salt withsilver oxide in aqueous or alcoholic solution followed by neutralizationwith the desired acid. The quaternary iodides may be converted to thechlorides by refluxing with an excess of methanolic hydrogen chloride,the iodide anion being removed as methyl iodide.

The 2-(disubstituted-aminoalkyl) 4,5,6,7 tetrachloroisoindolines areprepared conveniently by heating a mixture of tetrachlorophthalicanhydride with an excess of substituted-aminoalkylamine, andhydrogenating the phthalimide compound thus produced. The series ofreactions is illustrated as follows:

wherein R R R NR and n hayethe meanings as aforesaid.

The tetrachlorophthalic anhydride II and; excesssubstituted-aminoalkylamine IlI are preferably heated either with orwithout added solvent such as acetic acid at an elevated temperature offrom about to about 200 for from /2 to 3 hours, during which time theamide IV is first formed and on further heating is. converted to theimide V. The imide thus formed is hydrogenated with an agent such aslithium aluminum hydride, or by catalytic hydrogenation to theisoindoline VI.

Alternatively, the Z-(disubstituted aminoa1kyl)-4,5,6,7-tetrachloroisoindolines VI are prepared by treatingtetrachlorophthalimide or its potassium salt with ethylene or propylenedihalide such as the dibromide or dichloride to form the correspondingN-(halogenalkyl)-tetrachlorophthalimide which is treated with thedesired secondary amine to formN-(substituted-aminoalkyl)-tetrachlorophthalimide which is then reducedas described above to the 4,5,6,7 tetrachloro2-(substituted-aminoalkyl)-isoindoline VI.

Alternatively, the isoindolines VI may be formed b treating potassium1,2,3,4-tetrachlorophtl1alimide in dimethyl formamide solution with asubstituted-aminoalkyl halide followed by reduction according to thesteps:

ll Cl The quaternary N-(substituted-aminoalkyl)-tetrachloroisoindolinesdescribed herein are useful as ganglionic blocking agents and may beadministered either parenterally or orally and are of particularinterest for oral administration. For the purpose of administration, thecompounds may be made up in the form of tablets, ampoules and otherdosage forms. Any suitable carrier or vehicle may be employed, e.g.,water, gelatin, starch, magnesium stearate, talc, vegetable oils, benzylalcohol, gums, polyalkylene glycols, petroleum jelly, cholesterol orother known carrier substances for medicaments.

Substitution of four nuclear chlorine atoms inZ-diethylaminoethyl-isoindoline dimethiodide results in an unexpectedand remarkable enhancement of the ganglionic blocking activity. Thus,the activity of Z-dimethylaminoethyl-4,5,6,7-tetrachloroisoindolinedimethiodide is eighteen fold greater than that ofZ-diethylaminoethyl-isoindoline dimethiodide. The quaternized2-di(lower)alkyl aminoalkyl-4,5,6,7-tetrachloroisoindolines are moreactive than the quaternized2-piperidinoethyl-4,5,6,7-tetrachloroisoindolines. The methyl quaternarysalts of 4,5,6,7- tetrachloro-2-(2-dimethylaminoethyl)-isoindolineexhibit especially marked ganglionic blocking properties.

The activity of the quaternized tetrachloroisoindolines expressed as theratio of the dose required to give 50 percent inhibition of thenictitating membrane in the cat as compared to the knownZ-diethylaminoethyl-isoindoline dimethiodide is summarized below, thetests being carried out according to the procedure of Acheson andPereia, Exp. Pharm. and Therap. 87:273 (1946).

The invention extends also to Z-(disubstitutedaminoalkyl)-4,5,6,7-tetrachloroisoindolines and their acid additionsalts which serve as intermediates for the preparation of the quaternaryderivatives.

The invention is described in greater detail in the examples that followwhich are presented by way of illustration and not of limitation. Partsby Weight bear the same relation to parts by volume as do grams tomilliliters. Temperatures are uncorrected and expressed in degreescentigrade.

Example 1 50 parts by weight of 1,2,3,4-tetrachlorophthalic anhydride isadded with stirring and cooling to 30 parts by volume ofdimethylaminoethyl amine. The mixture is heated at 170 for 45 minutesand the oily residue then dissolved in 200 parts by volume of hotethanol. On

cooling, N (dimethylaminoethyl) 1,2,3,4 tetrachlorophthalimideseparates. It crystallizes from ethanol and melts at 184-186.

6 parts by weight of N-(dimethylarninoethyl)-1,2,3,4-tetrachlorophthalimide is extracted continuously with 300 parts byvolume of dry ether in which have been dissolved 3.1 parts by weight oflithium aluminum hydride. After 48 hours the excess lithium aluminumhydride is destroyed by cautious addition of 9 parts by volume of ethylacetate while stirring. There is then added in succession with stirring3 parts by volume of water, 6 parts by volume of 15 percent aqueoussodium hydroxide and 9 parts by volume of water. The granularprecipitate of lithium and aluminum salts are filtered and washed withether. The ether is distilled off, yielding the crude, oily 4,5 ,6,7tetrachloro-2-(Z-dimethylaminoethyl)-isoindoline. The above base isdissolved in 25 parts by volume of 90 percent ethanol and refluxed 2hours with 6 parts by volume of methyl iodide.4,5,6,7-tetrachloro-2-(2-di methylaminoethyl) isoindoline dimethiodideseparates during the reaction. It is collected by filtration andrecrystallized from a mixture of ethanol and Water; M.P.- 244-246.

4,5,6,7 tetrachloro-Z-(Z-dimethylaminoethyl)-isoindoline dimethochlorideis prepared by shaking an aqueous solution of the dimethiodide with anexcess of freshly prepared silver chloride and evaporating to drynessthe aqueous solution after removal of the silver salts. 4,5,6, 7tetrachloro 2-(2-dimethylaminoethyl) -isoindoline dimethochloride isrecrystallized from ethanol-ethylacetate; M.P. 276-280.

3.6 parts by weight of4,5,6,7-tetrachloro-2(dimethylaminoethyl)-isoindoline is refluxed in 50parts by volume of ethanol with 3.5 parts by weight of dimethyl sulfatefor 2 hours. On cooling, the methosulfate crystallized.Recrystallization from ethanol-water yielded 4,5,6,7-tetrachloro 2(dimethylaminoethyl) -isoindoline dimethosulfate, melts at 224-227.

Example 2 3.9 parts by weight of dimethylaminoethylamine is added withstirring to a suspension of 10 parts by weight of1,2,3,4-tetrachlorophthalic anhydride in 35 parts by volume of aceticacid. Heat is evolved as the anhydride dissolves. After the reactionmixture has been refluxed 3 hours, most of the acetic acid is distilledoff. While the residue is stirred with 50 parts by volume of water,concentrated ammonia is added until the mixture becomes alkaline. The N(dimethylaminoethyl) l,2,3,4-tetrachlorophthalimide is filtered anddried. It is pure enough for further reaction without recrystallization.

6 parts by weight of N-(dimethylaminoethyl)-l,2,3,4-tetrachlorophthalimide is pulverized and added to a Wellstirred solutionof 3.1 parts by weight of lithium aluminum hydride in ether in 300 partsby volume of dry ether. The mixture is stirred for 24 hours after whichthe reaction mixture is Worked up as described in Example 1.

Example 3 4,5,6,7 tetrachloro-2-(diethylaminoethyl)-isoindo1inedimethochloride; M.P. 202-207".

Other salts may be prepared by converting the iodide salt to thequaternary base and neutralizing with the desired acid. For example, thetartrate salt may be made by suspending 2 parts by weight of4,5,6,7-tetrachloro-2-(2- diethylaminoethyl)-isoindoline dimethiodide in20 parts by volume of water and stirring with parts by weight of moistsilver oxide for 24 hours. The silver salts are removed, a 20 percentaqueous tartaric acid solution is added until the basic solution becomesneutral to phenolphthalein and the aqueous solution evaporated todryness in vacuo. The residue is dissolved in a small amount of hotabsolute ethanol and ethyl acetate added to turbidity. Cooling givesfine needles of the highly Water soluble 4,5,6,7-tetrachloro 2(Z-diethylaminoethyl)-isoindoline dimethotartrate dihydrate, M.P.200-202".

Example 4 2 parts by weight of4,5,6,7-tetrachloro-2-(Z-diethylaminoethyD-isoindoline is refluxed for 4hours with 1.57 parts by Volume of dimethyl sulfate in parts by volumeof ethanol. Ethyl acetate is added to precipitate a syrup which slowlycrystallizes on standing at 5. The solid is recrystalized from ethanoland melts at ZOO-202. The product is 4,5,6,7-tetrachloro 2(2-diethylaminoethyl)- isoindoline dimethosulfate.

Example 5 10 parts by weight of potassium 1,2,3,4-tetrachlorophthalimideis dissolved in 50 parts by volume of dimethylformamide at 80. 10 partsby volume of N-(2- chloroethy1)-piperidine is added slowly. Afterminutes at this temperature an additional 5 parts by volume ofN-(Z-chloroethyl)-piperidine is added and heating continued for minutes.The reaction mixture is poured into water to yield a gummy materialwhich is crystallized To a stirred solution of 4.5 parts by weight of3-dimethylaminopropylamine in 100 parts by volume of benzene is added 10parts by weight of tetrachlorophthalic anhydride. The intermediatephthalimic acid (M.P. 195- 6") soon comes out of solution. It is notisolated but redissolves as continued refluxing causes lactamization tothe phthalimide. After 12 hours the benzene is evaporated, leaving aresidue of N-(3-dimethylarninopropyl)- 1,2,3,4-tetrachlorophthalimidewhich on recrystallization from ethanol melts at l25127. The steps ofreduction and quaternization of the resulting isoindoline is carried outas described in Example 1 to yield 4,5,6,7-tetrachloro- 2 (3dimethylaminopropyl) isoindoline dimethiodide which afterrecrystallization from 90 percent ethanol melts at 228-230 (dec.).

Conversion to the corresponding dimethochloride is effected by shakingwith silver chloride as described in Example 1. The dimethochloride isobtained also by direct quaternization of the isoindoline by bubblingmethylchloride into a boiling methylethylketone solution of theisoindoline. 4,5,6,7-tetrachloro 2 (3 dimethylaminopropyl)-isoindolinedimethochloride separates during the reaction and afterrecrystallization from ethanol-ethylacetate melts at 252-254 (dec.).

1 part by weight of4,5,6,7-tetrachloro-2-(3-dimethylaminopropyl)-isoindoline and 1.1 partsby volume of dimethylsulfate in 15 parts by volume of ethanol isrefluxed for 2 hours. The ethanol is removed in vacuo and addition ofethyl acetate causes separation of the 6 crystalline quaternary salts.It is recrystallized from an ethanol-ethyl acetate mixture to yield thepurified 4,5,6,7- tetrachloro 2 (3-dimethylaminopropyl)-isoindolinedimethosulate; M.P. 1658 (dec.).

Example 7 115 parts by weight of 3-diethylaminopropylamine is reactedwith 20 parts by weight of tetrachlorophthalic anhydride in benzene asdescribed in Example 6. The intermediary phthalimide is reduced withlithium aluminum hydride and the resulting product quaternized withexcess methyliodide as described in Example 1. The quaternary salt thusobtained is recrystallized from ethanolwater to yield4,5,6,7-tetrachloro 2 (3 diethylaminopropyl)-isoindoline dimethiodide;M.P. 215-220 (dec.).

Example 8 To a stirred suspension of 36 parts by Weight oftetrachlorophthalic anhydride and parts by volume of acetic acid isadded 14.3 parts by weight of 1-(3-aminopropyl)-pyrrolidine. The mixtureis refluxed for 3 hours, cooled and a small amount of insoluble materialremoved by filtration. The filtrate is reduced in volume to 1 quarter bydistillation, 100 parts by volume of water are added and the mixturemade basic with ammonia. The

material which separates is filtered oil and recrystalized I Example 910.5 parts by weight of 1-(2'-aminoethyl)-morpholine are added dropwisewith stirring to a solution of 20 parts by weight of3,4,5,6-tetrachlorophthalic anhydride in 100 parts by volume of aceticacid. The reaction mixture is refluxed for 2 hours, then of the aceticacid is removed in vacuo. The residue is diluted with water and madebasic with ammonia, precipitating the imide. The imide is filtered andafter recrystallization from ethanol, N-(2-morpholinoethyl)-3,4,5,6-tetrachlorophthalimide melts at 165-167.

20 parts by weight of N-(2-morpholinoethyl)-3,4,5,6-tetrachlorophthalimide are slurried with anhydrous ether and addeddropwise to a suspension of 5.8 parts by weight of lithium aluminumhydride in 250 parts by volume of anhydrous ether. After refluxing for18 hours, the reaction mixture is decomposed with 75 parts by volume ofethyl acetate followed by 5.8 parts by volume of water, 11.6 parts byvolume of 15 percent sodium hydroxide and finally 17.4 parts by volumeof water. The reaction mixture is then diluted with ether and filtered.Evaporation of the ether yields a semi-solid residue. The thus obtained4,5,6,7-tetrachloro-2-(2' morpholinoethyl)-isoindoline is purified byrecrystallization from ethanolwater, M.P. -112.

The corresponding dimethiodide is prepared by refluxing a solution of 4parts by weight of 4,5,6,7-tetrachloro-2-(2-morpholinoethyl)-isoindoline in 10 parts by volume of dimethylformamide with 15 parts by volume of methyl iodide for 4 hours.

Some solid material is filtered off and ethyl acetate added to thefiltrate. The resulting gummy material is crystallized by rubbing withethyl acetate. Purification of the thus obtained4,5,6,7-tetrachloro-2-(2-morpholino ethyl)-isoindoline dimethiodide isachieved by recrystallization from aqueous ethanol-ethyl acetate; M.P.189- 192".

7 What is claimed is: 1. A compound of the formula:

wherein R and R are members selected from the group consisting of loweralkyl radicals and when taken together, comprise the alkylene andoxaalkylene radicals containing from 4 to 5 carbon atoms, and n is awhole number from 2 to 3.

2. N (2 dimethylaminoethyl) 1,2,3,4-tetrachloroph'thalimide.

3. N-(Z-diethylaminoethyl)-1,2,3,4 tetrachlorophthalimide.

References Cited in the file of this patent UNITED STATES PATENTS BohrerJune 22, 1948 OTHER REFERENCES Sakurai: C.A., vol. 26, July-September1932, page 4542 Moore and Rapala: J.A.C.S., 68: 1657 (1946).

Uffer et al.: C.A., vol. 43, January-March, 1949, page UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,025,300 March 13,1962 Charles Ferdinand Huebner It is hereby certified that error appearsin the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 2, lines 10 to 20 formula III, should appear as shown belowinstead of as in the patent:

a mca N- 2 same column, lines 40 to 45, formula VI, should appear asshown below instead of as in the patent:

1 2 N(CH NR R Signed and sealed this 17th day of September 1963.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD

1. A COMPOUND OF THE FORMULA
 4. N-(2-PIPERIDINOTHYL) -1,2,3,4 -TETRACHLOROPHALIMIDE. 